Background: Telomere shortening limits the proliferative capacity of human fibroblast to 50-75 cell divisions by inducing senescence or apoptosis. There is growing evidence that telomere shortening impacts on human ageing, diseases, and cancer: (i) Telomere shortening occurs in almost all human tissues during human ageing; (ii) Telomere shortening is accelerated in chronic human disease; (iii) Telomere shortening and telomerase reactivation occur in the vast majority of human cancers; (iv) Telomerase mutations are associated with a shortened lifespan, organ failure, and increased cancer risk in humans. (see 
Textbook)
Previous work: Using telomerase knockout mice as a model system, we have shown that
- telomere shortening impairs the maintenance of organ system with high rates of cell turnover and this is associated with a shortened lifespan
- telomere shortening limits stress responses and organ regeneration in response to injury
- telomere shortening has dual role in cancer formation: It induces chromosomal instability and increases the rate of cancer initiation; in contrast, telomere shortening suppresses the progression of tumours
- telomere shortening induces cell intrinsic checkpoint that limit the maintenance (self renewal) and function of stem cells during ageing (Figure 1)
- inhibition of checkpoint responses can improve stem cell function and extend lifespan of telomere dysfunctional mice
- telomere shortening also induces cell extrinsic alterations of the environment and the stem cell niche leading to a decrease in stem cell function
(see 
References)
- Figure 1: (A) Telomere shortening leads to loss of telomere capping function. The picture shows a metaphase form a bone marrow cell of telomerase knockout mice. Telomeres are marked in red. Normally each chromosome end is capped by a telomere (yellow arrow). When telomeres become critically short, they lose capping function at the telomere (red arrow points to telomere-free ends). The cell recognizes telomere free ends as DNA-damage. Checkpoint response (senescence/apoptosis) are induced. In addition, DNA-repair pathways get activated. This leads to chromosomal fusions (circled chromosome pair is showing a p-p-arm fusion) and the induction of chromosmal instability. (B) In vivo, telomere shortening is associated with accelerated stem cell ageing. The photographs show the loss of intestinal stem cells in basal crypts of the small intestine in ageing telomerase knockout mice. The arrows point to the basal crypts, which contain the stem and progenitor cells.
